Bioassay-guided fractionation of crude extracts from marine invertebrates and higher plants has yielded compounds with substantial antitumor and anti-HIV activity. Purification and characterization efforts on proteins, producing novel differential cytotoxicity profiles in the NCI screen, from sponges including Tethya ingalli (tethyatoxins A and B) are in progress. Several distinct groups of sponges have been identified by use of the COMPARE algorithm as having similar types of activity. An anti- HIV protein (niphatevirin) from the sponge Niphates digitalis has been purified and characterized. Niphatevirin appears to act by binding to the cellular receptor molecule CD4, thereby blocking syncytium formation. A complex series of saponins, elliptosides A-J, has been purified from the plant Archidendron ellipticum (Leguminosae) and characterized by NMR, MS, and chemical studies. The elliptosides show selective cytotoxicity to renal cancer cell lines in the NCI cancer screen, and are active in experimental in vivo therapeutic models. A novel type of cytotoxic macrolide, salicyli- halamide, has been isolated from the sponge Haliclona sp. and its structure has been determined.